Approximately 1 million people in the United States are at risk for development of iron overload, attributable primarily to the genetic disorder known as hemochromatosis (HH). Once considered a rare disease, HH is now recognized as one of the most common autosomal recessive disorders, occurring in approximately 5 persons per 1,000 in populations of northern European descent. Most patients with hemochromatosis are homozygous for the C282Y mutation in the HFE gene. This inborn error of iron metabolism is characterized by excessive dietary iron absorption and progressive accumulation of iron in the body, typically reaching toxic levels by mid life. The overall goal of this research is to answer te question, What role do genetic modifiers play in determining iron accumulation in persons homozygous for the HFE C282Y genotype? With assistance from a R24 seeding grant, we have established an international collaborative research team, developed and validated a phenotyping protocol and performed preliminary studies. This full R24 project will utilize current capabilities of exome sequencing followed by targeted sequencing of iron-related genome regions and single nucleotide variants to identify rare and common causal variants associated with severe or mild iron expression in hemochromatosis patients. An efficient selective genotyping study design will be used for which three comparison groups have been identified, HFE C282Y homozygotes with normal or minimally elevated iron stores (low expression) at the time of first diagnosis, HFE C282Y homozygotes with markedly increased iron stores (high expression) at diagnosis, and a third group of non-hemochromatosis subjects who have normal iron stores and no HFE mutations. A follow-up validation study will be preformed and a model will be developed for predicting risk of high expression. This research will provide insight into possible genetic contributions to susceptibility or resistance to iron overload, help to understand the significant variation in iron loading in different individuals with this disorder and the relationship to clinical manifestations, and ultimately lead to development of innovative prevention and treatment strategies tailored to the individual. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page